The development of sustainable treatments for human illnesses is one of the foremost challenges of the present day. While organocatalytic reactions are a potential means to this end, there is a need to develop organocatalytic reactions with tangible applications as drug development processes. The long-term goal of this research program is to demonstrate the effectiveness of organocatalytic reactions in the synthesis of small molecules that treat illnesses in humans. The overall objective of this application, which is fundamental to ultimately achieving this long-term goal, is to develop organocatalytic reactions that generate products with broad utility in the synthesis of therapeutic compounds. There are two central hypotheses that underlie the proposed research: 1) organocatalytic 2-carbon-heteroatom bond-forming reactions and organocatalytic 1- carbon-heteroatom bond-forming reactions can be combined as new organocascade reactions, and 2)) organocascade reactions can be adapted to produce useful heterocycles. The rationale for the proposed research is that once organocatalytic reactions generate synthetic building blocks of therapeutic compounds, they can be exploited in the synthesis of therapeutic compounds. As this research proposes new methods to be employed in the synthesis of compounds that can improve human health, it is relevant to the NIH's mission of fostering the development and application of new strategies for improving health. The above hypotheses were based on preliminary data from our laboratories and are a feasible extension of published data, and will be tested by two specific aims: 1) Develop organocatalytic carbon-nitrogen bond-forming reactions that generate useful synthons; and 2) Develop novel organocatalytic oxa-Michael additions. For both aims, catalysts and substrates will be synthesized, and starting with conditions reported for the closest relevant examples, reaction conditions will be systematically optimized to achieve efficient transformations. The proposed research is innovative, because it entails the development of organocatalytic transformations that represent new, improved methods for accessing important substructures of medicinal compounds. This is significant because it will establish the viability of organocatalytic reactions as economical, environmentally friendly drug development processes, which are vital to sustaining human health.